Benzimidazole-2-carbamates substituted on the benzene ring with an acyloxyalkyl group

ABSTRACT

BENZIMIDAZOLYL CARBAMIC ACIDS AND SUBSTITUTED ON THE BENZENE NUCLEUS BY CARBOXYLATED ALKYL AND ALKOXY GROUPS ARE DISCLOSED AS HAVING ACTIVITY AGAINST HELMINTHIASIS IN ANIMALS. THEY MAY BE PREPARED SYNTHETICALLY STARTING WITH AN APPROPRIATE P-AMINOPHENYL ALKYL ALCOHOL, PROCEEDING THROUGH THE ALCOHOLIC PHENYLENE DIAMINE TO A HYDROXYALKYL-2-CARBOMETHOXYAMINOBENZIMIDAZOLE.

United States Patent ce 3,578,676 BENZIMIDAZOLE-Z-CARBAMATES SUBSTITUTEDON THE BENZENE RING WITH AN ACYLOXY- ALKYL GROUP George L. Dunn, Wayne,Pa., assignor to Smith Khne & French Laboratories, Philadelphia, Pa. NoDrawing. Filed June 21, 1968, Ser. No. 738,842 Int. Cl. C07d 49/38 US.Cl. 260-3092 9 Claims ABSTRACT OF THE DISCLOSURE Benzimidazolyl carbamicacids and substituted on the benzene nucleus by carboxylated alkyl andalkoxy groups are disclosed as having activity against helminthiasis inanimals. They may be prepared synthetically starting with an appropriatep-aminophenyl alkyl alcohol, proceeding through the alcoholic phenylenediamine to a hydroxyalkyl-Z-carbomethoxyaminobenzimidazole.

This invention relates to anthelmintic compositions containing benzenering substituted esters of benzimidazolyl carbamic acids, and to methodsfor producing anthelmintic activity using said esters.

According to one aspect of the invention, there are provided ananthelmintic composition and method of producing anthelmintic activitywhich utilizes as the essential active ingredient certain esters ofbenzimidazolyl carbamic acid represented by the general formula:

Formula I wherein:

R is alkyl straight or branched containing from one to six carbon atoms;cycloalkyl including alkyl cycloalkyl containing from three to sixcarbon atoms; alkenyl straight or branched chain containing from two tosix carbon atoms; alkynyl straight or branched containing from two tosix carbon atoms; phenyl; naphthyl, a or alkoxy straight or branchedcontaining one to ten carbon atoms; cycloalkoxy, includingalkylcycloalkoxy, containing 3 to 10 carbon atoms; alkenyloxy containingfrom two to ten carbon atoms; alkynyloxy containing from two to tencarbon atoms; phenyloxy; or naphthyloxy, u or p;

Y is alkyl straight or branched from one to six carbon atoms; cycloalkylfrom three to six carbon atoms; alkenyl straight or branched from one tosix carbon atoms; or alkynyl straight or branched from one to six carbonatoms, and

n is a whole integer from one to eight.

It is preferred to use as the active ingredient of the novelcompositions of this invention, compounds as shown in Formula 11 below:

Formula II wherein:

R and Y are lower alkyl containing from one to three carbon atoms, and

n is a whole integer from one to five.

3,578,676 Patented May 11, 1971 For example, a novel compound withinFormulas I and II of good eflicacy is 2-carbomethoXyamino-5-[3-acetoxypropyl]-benzimidaz0le which demonstrated 75.5% (replicated) reduction inWorm burden (activity) against the mouse pinworm at mg./ kg., and 51%activity at 10 mg./kg.

The novel alcohol substituted o-phenylene diamine intermediatesdisclosed herein are also a part of this invention, by virtue of theiruse in making the anthelmintic esters of Formula I. These alcohols havethe general structural formula:

NHz

wherein: n is an integer from one to eight.

Examples of specific compounds falling within Formula I are:

2-carbomethoxyamino-5- 3-acetoxypropyl] -benzimidazole Z-acetamido-S-[3-acetoxypropyl] benzimidazole 2-carboethoxyamino-5- Z-acetoxyethyl]-benzimidazole 2-propionarnido-5- [Z-acetoxyethyl] -benzimidaz0le2-carbobutoxyamino-5-[ l-acetoxymethyl] -benzimidazole 2-butyramido 5-l-acetoxymethyl] -benzimidazo1e 2-carbobutoxyamino-5- l-acetoxymethyl]-benzimidazo1e 2-valeramido-5- l-acetoxymethyl] -benzimidazole2-carboamyloxyamino-5-[3-propionyloxypropyl1- benzimidazole2caproylamido-5- 3-propionyloxypropyl] -benzimidazole2-carbohexyloxyamino-5' [4-butyryloxybutyl] benzimidazole2-heptanoylamido-5- [4-butyryloxybutyl] -benzimidazole2-carbocyclopropyloxyamino-S-[3-butyryloxypropy11- benzimidazole2-cyclopropylamido-5- B-butyryloxypropyl] -benzimidazole2-carbocyclobutyloxyamino-5-[2-propionyloxyethyl1- benzimidazole2-cyclobutaneamido-5- [Z-propionyloxyethyl] -benzimidazole2-carbocyclopentyloxyamino-S- 1 -acetoxymethy1] benzimidazoleZ-cyclopentaneamido-S- l-acetoxymethyl] -benzimidazole2-carbocycloheptyloxyamino-S- 3-acetoxypropyl1 benzimidazole2-cyclohexaneamido-5- 3-acetoxypropyl] -benzirnidazole2-carbocyclohexyloxyamino-5-[4-propionyloxybutyl1- benzimidazole2-cycloheptaneamido-5- [4-propionyloxybutyl] benzimidazole2-carboethoxyamino-5- 3 -cyclopropylcarboxypropyl] benzimidazole2-propionamido-5- 3-cyclopropylcarboxypropyl] benzimidazole2-carbopropoxyamino-5- [2-allylcarboxyethyl] -benzimidazole2-butyramido-5- [2-allylcarboxyethyl] -benzimidaz0leZ-carbobutoxyamino-S- [dimethallylcarboxymethyl] benzimidazole2-valeramido-5- [dimethallyloxymethyl] -benzimidazole2-carbophenoxyamino-5- 3-acetoxypropyl] -benzimidazole 2-phenoXamido-5-3-acetoxypropyl] -benzimid azole 2-carbonaphthyloxyamino-S-[2-propionyloxyethyl] benzimidazole 2-naphthylamido-5-[2-propionyloxyethyl] -benzimidazole 2-carbohexyloxyamino-S-acetoxymethylb enzimidazoleZ-heptanoylamido-S-acetoxymethylbenzimidazole 2-carboamy1oxyamino-5[Z-butyryloxyethyl] -benzimidazole Z-caproylamido-S- [Z-butyryloxyethyl]benzimidazole 2-carbobutoXyamino-5- [3 -propargylcarboxypropyl]benzimidazole 2-valeramido-5- [3 -prop argylcarboxypropyl]-benzimidazole Z-carb opropoxyamino-S- [4-vinylcarboxybutyl]benzimidazole 2-butyramido-5 [4-vinylcarb oxybutyl] -benzimidazole2-carboethoxyamino-5 [5 -methally1carboxyamyl] benzimidazole2-propionamido-5- [S-methallylcarboxyamyl] -benzimid azoleZ-car-bomethoxyamino-S- 6-ethinylcarboxyhexyl] b enzimidazole2-acetamido-5- [G-ethinylcarb oxyhexyl] -benzimidazole2-carboviny1oxyamino-5- [4-cyclopropylc arb oxybutyl] benzimidazole2-vinylamido-5- [4-cyclopropylcarboxybutyl]-benzimidazole Z-carboallyloxyamino-S- [3 -cyclobutylcarboxypropyl] benzimidazole2-allylamido-5- 3 -cyclobutylcarboxypropyl] -b enzimid azole 2-carbomethallyloxyamino- [Z-cycloamylcarboxyethyl] benzimidazoleZ-methallyamido- [2-cycloamylcarboxyethyl] -b enzimidazole2-carbodimethallyloxyamino-S- [cyclohexylcarboxymethyl] -benzimidazole2-dimetha1lylamido-5 [cyclohexylc arb oxymethyl] benzimidazole2-carboprop argyloxyamino-S- S-acetoxyamyl] benzimidazole Z-propargylamino-5 [5 -acetoxy amyl] -benzimidazole Z-carbobutynoxyamino-S-[4-propionyloxybutyl1- benzimidazole 2-b utyramido-S-[4-propionyloxybutyl] -benzimidazole 2-carbopentynoxyamino-5-[3-butyryloxypropyl1- benzimidazole Z-pentynamido-S [3 -butyryloxypropyl]-b enzimidazole Z-carbohexynoxyamino -5 [Z-valeryloxyethyl]-benzimidazole 2-hexyn amido-S- [2-valeryloxyehyl] -benzimidazole2-carbocyclopropyloxyamino-5 [Z-hexanoyloxyethyl] benzimidazole2-cyclopropyl amide-5 [2-hexanoyloxyethyl] -benzimidazole Z-carbocyclobutyloxyamino-S- [Z-actoxyethyl] -benzimidazole2-cyclobutylamido-5-[ Z-acetoxyethyl] -benzimid azole The compounds ofFormula I wherein R is alkoxy, and Y is alkyl may be prepared startingwith the appropriate p-aminophenyl alkyl alcohol. This intermediate isacylated with an appropriate anhydride, followed by nitration with redfuming nitric acid, to give the corresponding 3-nitro N, O-diacyl(aminophenyD-alkyl alcohol. Hydrolysis gives the corresponding3-nitro-p-aminophenyl alkyl alcohol. This latter intermediate is reducedto yield an alcohol substituted o-phenylenediamine. The diamineintermediate is converted, by the later-detailed thiourea sulfateprocess, which employs 2-methyl-2-thiopseudourea sulfate and methylchloroformate, to the corresponding 2-carboalkoxyamino-5-hydroxyalkylbenzimidazole, which is, in turn,acylated with an anhydride or an acid chloride in a non-polar solvent,like pyridine, to yield the corresponding S-acyloxyalkyl derivative of2-carbomethoxyaminobenzimidazole.

The compounds of Formula I in which R is a alkyloxy, and Y is cycloalkylare prepared, again starting with a p-aminophenyl alkyl alcohol, andtreating in the manner 4 just described until the final step ofesterifying the S-hydroxy alkyl compound, there upon substituting acycloalkyl acid chloride to yield a S-cycloalkylcarboxyalkyl derivative.

Similarly, when Y is alkyl and R is alkenyloxy or alkynyloxy, thecompounds are prepared in like manner except by using a thiourea reagenthaving terminal alkenyl or alkynyl moieties, in which the double ortriple bonds thereof are not conjugated with the C-X or 0 0 moiety.

The compounds of I in which Y is alkyl, and R is cycloalkyloxy are alsoprepared by the thiourea sulfate process, except that reagent contains aterminal cycloalkyl moiety in place of a linear or branched alkylmoiety.

The compounds of I in which Y is cycloalkyl, and R is also cycloalkyloxyare also prepared by the same process, employing a thiourea sulfatereagent with terminal cycloalkyl moieties to form theS-hydroxyalkyl-Z-carbomethoxyaminobenzimidazole intermediate, followedby esterification with a cycloalkyl acid chloride to yield 2,5-dicycloalkyl derivatives.

Compounds of Formula I in which Y is cycloalkyl and R is alkenyloxy oralkynyloxy, the compounds are similar- 1y prepared as described above,using thiourea sulfates wherein the terminal groups are cycloalkylmoieites, and the esterification step is carried out using unsaturatedacyl anhydrides or acid chlorides to yieldS-cycloalkylcarboxyalkyl-Z-carboalkenyloxy (or alkynyloxy)aminobenzimidazole.

The compounds of Formula I wherein R is alkyl, and Y is alkyl areconveniently prepared by starting with cyanamide, and reacting it with aselected acyl halide in pyridine, or other organic solvent, followed byreaction with the appropriate alcoholic o-phenylenediamine, to give thecorresponding benzene ring substituted 2-alkamidobenzimidazole.

The compounds of Formula I in which R is alkyl, and Y is cycloalkyl areprepared, again starting with an alcohol substituted o-phenylenediamine,and treating in the manner just described, until the finalesterification step, but substituting a cycloalkyl anhydride or acidchloride to yield a 2-cycloalkylamido derivative of a S-acyloxyalkylbenzimidazole.

Similarly, when Y is alkyl, and R is alkenyl or alkynyl, the compoundsare prepared in like manner except by using in the initial acylationacid chloride reagent having terminal alkenyl or alkynyl moieties, inwhich the double or triple bonds thereof are not conjugated with the 0:0moiety.

The compounds of I in which Y is alkyl and R is cycloalkyl are alsoprepared by the cyanamide process, except that the acyl halide reagentcontains a terminal cycloalkyl moiety in place of a linear or branchedalkyl moiety.

The compounds of I in which Y is cycloalkyl, and R is also cycloalkylare also prepared by the same process, employing an anhydride or acidchloride reagent having terminal cycloalkyl moieties to form theS-hydroxyalkyl- Z-cycloalkylamido benzimidazole intermediate, followedby esterification with a cycloalkyl acid chloride to yield the2,5-dicycloalkyl derivatives.

Compounds of Formula I in which Y is cycloalkyl and R is alkenyl oralkynyl, the compounds are similarly prepared as described above, usingacid chlorides wherein the terminal groups have alkenyl or alkynylmoieties, and the esterification step is carried out using a cycloalkylanhydride, or acid chloride, to yieldS-cycloalkylcarboxyalkyl-Z-alkenyl-(or Z-alkynyl) amidobenzimidazole.

A suitable process for making the anthelmintic compound for thisinvention employs a S-lower alkyl pseudothiourea sulfate in thecondensation step. The appropriate sulfate is treated with one to twoequivalents of a lower alkyl halo formate in aqueous solution, and thenby condensing with a suitable alcohol substituted 0- phenylenediamine,it yields the corresponding 2-carboxyamino-S-hydroxyalkyl benzimidazole.

The o-phenylenediamine reactants have alkyl alcohol substituents on thebenzene ring which correspond to the benzimidazole of the final productas defined in Formula I. The resulting benzimidazoles bear thesubstituents at the corresponding position of the benzene ring, which bysuitable esterification are converted to the herein claimed anthelminticcompounds. The nature of the condensation reaction is such that it isgenerally applicable to ophenylenediamines, regardless of the carbonchain length of the alkyl alcohol which appears on its benzene ring.

It will be readily apparent to one skilled in this art that certain ofthe substituted Z-aminobenzimidazole compounds (R or Y is branched) ofthis invention may have asymmetric carbon atoms, forming opticallyactive dand l-compounds. The connotation of the general formulaspresented herein is intended to include the separated dor l-opticalisomers, as well as racemic mixtures of these isomers.

If desired, the isomers may be separated for individual use byresolution methods known to the art, such as fractional crystallizationof the l-tartrate salts of the carbamates. Alternatively, a synthesisstarting with an optically active side chain may yield the desiredoptical isomer.

The compounds of Formula I being weak bases will normally form saltswith inorganic and organic acids. Accordingly, the nontoxic salts formedwith pharmaceutically acceptable strong inorganic and organic acids maybe alternatively employed in the compositions of the invention. Othernontoxic molecular complexes known to eiist that can be derived fromcompounds of Formula I may also be used in this invention, since theanthelmintic activity rests in the benzimidazolyl carbamic acidstructure itself.

Benzimidazolyl carbamates of Formula I have been found to possess usefulanthelmintic properties, that is, broad spectrum activity againstparasites of warm blooded animals, including both mature and immatureparasitic forms. In particular, these compounds have been found toexhibit activity against various helmintic infections of the intestinaltract of economically important animals, coupled with low systemictoxicity to the host animal.

For example, the disclosed compounds are generally effective in clearingmice of worm infections for laboratory purposes, among others: SyphaczaObvelata and Aspicularis tetraptera (mouse pinworm).

Other susceptible helminths include Toxocam canis, found in naturallyinfested dogs. Also, parasitic to this host are Arzcylostoma carnium, Trichurz's vulpis (whipworm), and Phsalaptera spp.

Compounds of Formula I are eflicacious against parasitic gastroenteritisin sheep, such as Haemonchus cnt0r tus, Ostertagia spp.,Trichostrongylus spp., Nematodirus spp., Trichuris ovz'a, Cooperia spp.,and Strongyloides papillosus. Bzmostomum trigonocephalumandOesophagostomum spp., are other important parasites of sheep.

Animals of low weight are treated with unit doses ranging no higher thana few milligrams; Whereas animals of high body weight, such asruminants, require proportionately larger unit doses ranging up toseveral grams. Preferably, a single dose is administered daily for eachanimal species based on the weight of that species.

The amount of ingredient administered will depend on the weight of thehost, but will usually be between about 1 mg./kg. and 500 mg./kg. ofbody weight daily.

For example, Z-carbomethoxyamino-S [3 acetoxypropyl]benzimidazole at anoral daily dose of 50 mg./kg. (replicated) tested in clearing mice ofnatural pinworm infection, following generally the method of McCowen etal., reported in the American Journal of Tropical Medicine, 6, 894(1957), gave a 75.5% result in terms of worms cleared. At mg./kg.,showed a 51% reduction in the pinworm burden. Its LD in mice exceeds 500mg./

In practice, a phamacologically active compound of strucaural Formula Iis usually formulated with a nontoxic carrier therefore to giveanthelmintic compositions of this invention. The carrier may be anorally ingestible container for the active ingredient, for example, ahard or soft gelatin capsules; or it may be a pharmaceuticallyacceptable diluent or excipient of the kind normally used in theproduction of medicaments, ready for use, for example maize starch,terra alba, lactose, sucrose, calcium phosphate, gelatin, talcum,stearic acid, magnesium stearate, dextrin, agar, pectin or acacia.

Exemplary of liquid carriers are peanut oil, olive oil, sesame oil, andwater. Similarly, the carrier or diluent may include a time materialsuch as glyceryl monoste-arate or glyceryl distearate alone or with awax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule, or C0111? pounded in the form of a troche or lozenge.The amount of solid carrier will vary widely but preferably will be fromabout 25 mg. to about 3 gm. If a liquid carrier is used, the preparationmay be in the form of a soft gelatin capsule, placed in an ampule or inliquid suspension.

The compositions are most often made u in a form suitable for internaladministration and may therefore take the form of a liquid, for example,an emulsion or a sterile solution or suspension in water, oil, such asarachis oil, or other liquid.

The compositions are advantageously made up in a dosage unit formadapted for the desired mode of administration. Thus, for the preferredoral administration the dosage unit may take the form of a suspension,tablet, packaged powder, bolus, or encapsulated powder. The quantity ofactive ingredient in each dosage unit will be such that one or moreunits are required for each therapeutic administration.

As previously mentioned, the compounds of Formula I have generalanthelmintic activity and accordingly a further and most importantaspect of this invention provides a method of treating helminticinfections in an animal which comprises administering, usually orally,to the animal in a suflicient nontoxic, but effective, dose ananthelmintic compound falling within the definition of Formula I,generally in the form of a pharmaceutical or veterinary composition ashereinbefore described. The daily dose range commonly used is from about1 rug/kg. to about 500 mg./kg. depending on the species of host andregimen used. One dose per day administration is preferred but up tofive of the dosage units described above may be used if desired.

Where tableting is used, the resulting tablets are then coated withmethyl methacrylate to form an enteric coating, Le. a coating which issubstantially insoluble in gastric secretion but substantially solublein intestinal fluids.

It will be appreciated that the actice ingredient used in theformulation of the tablets described above may be replaced with othercompounds of Formula I having the necesary anthelmintic activity.Furthermore, other materials may be used to form the enteric coating,for example other synthetic plastic materials such as methyl acrylate,cellulose derivatives, hydrogenated caster oil or phthalates.

The compositions thusly prepared are administered, usually orally, to aninfected host from 1-5 times daily for anthelmintic activity.

The following examples illustrate syntheses which may be employed informulating the compositions of the invention but are not consideredlimiting the invention described herebefore.

EXAMPLE 1 Preparation of 2-carbomethoxyamino-5-(3-acetoxypropyl)benzimidazole 3-(p-aminophenyl)propyl alcohol (13 g., 0.09 mole) and10.1 g. (0.099 mole) of acetic anhydride are admixed with stirring andheated at reflux for 30 minutes. Acetyl chloride (7.8 g.) is added, andthe mixture is refluxed for an added hour. The mixture is evaporated invacuo to give a solid residue. The residue is dissolved in 43 ml. ofacetic anhydride and then 10.5 ml. of 70% HNO is added dropwise, over45-50 minutes with stirring. The exothermic reaction temperature ismaintained between 9 and 11 C., by occasional cooling with a DryIce-water acetone bath. After stirring for an added 15 minutes at 10 C.,the mixture is poured into 400 ml. of H at 0 C., and after stirring for30 minutes a yellow brown solid is filtered otf, and air driedovernight.

This crude material (the nitroamino-diacyl derivative of the startingmaterial) weighs 19 g., M.P. 73-76" C.

The aforedescribed intermediate is suspended in 350 ml. of aqueous NaOHand the mixture refluxed for 2.5 hours, cooled, and extracted with etherseveral times. After filtration, the solvent is evaporated. An infraredspectrum indicates, cleavage of the acetyl groups, giving the4-amino-3-nitropheny1 propyl alcohol.

The above disubstituted phenylpropyl alcohol (7.6 g.) is dissolved in200 ml. ethanol, 1.5 g. of palladium catalyst (5% by weight on charcoal)is added, and the mixture is shaken under 60 p.s.i. hydrogen (initial)at room temperature for two hours in a Paar apparatus.

The catalyst is removed by filtration on Supercel. The filtrate isevaporated to dryness, giving 6.3 g. of a purplish looking semi-solid,whose infrared spectrum is consistent wtih diaminophenyl propyl aclohol.

To 12.4 g. (0.163 mole) of thiourea in 6.2 ml. of Water, is added,dropwise, 14 g. (0.11 mole) of dimethyl sulfate with stirring. Themixture becomes warm and colorless, and is refluxed gently for 30minutes, during which time a white crystalline solid appears. Thereaction mixture is then cooled at 20 C., yielding2-methyl-2-thiopseudourea sulfate.

Methylchloroformate (7.18 g., 0.076 mole) is added in one portion to10.56 g. of 2-methyl-2-thiopseudourea sulfate. To this mixture is addedabout 12 ml. of aqueous NaOH, at a rate which maintains the temperatureno higher than 5 C., with a resulting pH of 7.0-7.5. Acetic acid (5 ml.)then is slowly added bringing the pH to 5.0-5 .5.4-hydroxypropyl-o-phenylenediamine (6.2 g., .037 mole) dissolved in 25ml. of 50% aqueous ethanol is added in one portion, then the mixture isslowly warmed until reaching a gentle reflux temperature at 85 C., andis refluxed for an additional minutes.

The precipitate which forms is filtered off after cooling the reaction,washed with cold aqueous ethanol and allowed to dry overnight, yielding7.3 g. of a tan crude product.

The product is recrystallized from 400 ml. of 50% aqueous ethanol, andthen from anhydrous ethanol to give, after air drying, 2.1 g. of2-carbomethoxyamino-5-(3- hydroxypropyl)-benzimidazole, M.P. of 285(d.).

To a flask equipped with a magnetic stirring bar and condenser, thesubstituted benzirnidazole (0.5 g., 0.002 mole), 0.61 g. of aceticanhydride, and 12 ml. of pyridine are added. Upon stirring for one hour,the solid goes into solution, and is allowed to stir overnight. Thesolution is poured into 200 ml. of water, the pH (6.0) of the resultingcloudy mixture is adjusted to 5.0-5.5 with glacial acetic acid causingmore solid to precipitate.

After several hours, the solid is collected and recrystallized from 95%ethanol (denatured with methanol), yielding the desired end product,methyl-5-(3-acetoxypropyl)- 2-benzimidazolyl-carbarnate, 0.45 g., M.P.205207 C.

EXAMPLE 2 When the following substituted o-phenylenediamines aresubstituted for the 4-hydroxypropyl-o-phenylenediamine in the procedureof Example 1, the corresponding listed products are obtained:

4-(5-hydroxyamyD-o-PDA When the following substituted acyl anhydridesand/ or o-phenylenediamine (PDA) substituted for the acetic anhydride inthe procedures of Examples 1 and 2, corresponding listed products areobtained:

Starting material 4-hydroxymethyl-o-PDA and propionyl anhydride.

4-(2-hydr0xyethyD-o-PDA and propionyl anhydride.

4-(3-hydroxypropyl)-o PDA and propionyl anhydride. (4-hydroxybutyD-o-PDAand propionyl anhydride.

Products 2carbomethoxyamino-5-[l-propionyloxymethyH-benzimidazole.

Z-carbomethoxyamino-5-[2 propi0ny1oxyethyll-benzimidazole.

2-carbomethoxyarnino-5-[ZipropinyloxypropyH-benzimidazole.

2-carbomethoxyamino-Ht-propionyloxybutyH-benzimidazole.

2-earbometh0xyamino-6[5propi0nyloxyamyl]-benzimidazole.

and propionyl auhydride.

2-carbomcthoxyamino-S-[l-butyryloxy- (4-hydroxymethyD-o-PDA and butyrylanhydride. methyH-benZimidazole. 4-(2-hydr0xyethyD-o-PDA2-carbomethoxyamiuo-5{2-butyryloxyand butyryl anhydride.ethyll-benzimidazole. 4(3-hydroxypropyl)-0-Z-carbomethoxyamino-fi-[3-butyryloxy- PDA and butyrylanpropyl]-oenzimidazole. hydride. 4-(4-hydroxybutyD-o-PDA2-carbomethoxyamino-5-[4-butyryloxyand butyryl anhydride.butyH-benzimidazole. 4-(5-hydroxyamyD-o-PDA2-carbomethoxyamino-5-[S-butyryloxyand butyryl anhydride.amyl]-benzimidazole.

EXAMPLE 4 When the following acyl halides are combined with S-loweralkyl pseudothiourea sulfate in place of the methyl chloroformate ofExample 1, the corresponding listed products are obtained:

Starting material Products .Allyl chloroformate 12-earboallyloxyamino5-[3-acetoxypropyl]- benzimidazole.

1 Available from Ohemetron Corp, Chicago, Ill.

EXAMPLE 5 Preparation of 2-isobutyramido-5-[3-acetoxypropyl1-benzimidazole 4-(3-hydroxypropyl)-0-phenylenediamine, prepared asdescribed in Example 1, and 1 g. cyanamide are reacted in the followingmanner: A cold (0-50 C.) solution of cyanamide (1.0 g., 0.0238 mole) in20 ml. of dry pyridine is treated dropwise with isobutyryl chloride(2.53 g., 0.0238 mole). When addition is complete, the dark red mixtureis stirred for 10 minutes at 05 C., and then for 35 minutes at roomtemperature. The 4-(3-hydroxypropyl)-o-phenylenediamine (7.9 g., 0.0476mole) was added in one portion; the mixture is allowed to stir 35minutes at room temperature and then is heated on a steam bath for 2.5hours. The mixture is cooled in ice, diluted with 20 ml. of water, andthe precipitated solid is collected. The solid is washed well with waterand dried at 60 C., to give a good yield of5-(3-hydroxypropyl)-isobutyramidobenzimidazole.

To a flask equipped with a magnetic stirring bar and condenser, thesubstituted benzimidazole (0.5 g., 0.002 moles) 0.61 g. of aceticanhydride, and 12 ml. of pyridine are added. Upon stirring for one hour,the solid goes into solution and then the solution is allowed to stirovernight. The solution is poured into 200 ml. of water, the pH (6.0) ofthe resulting cloudy mixture is adjusted to 5.0-5.5 with glacial aceticacid, causing more solid to precipitate.

After several hours, the solid is collected and recrystallized from 95%ethanol yielding the desired end product,2-isobutyramido-5-[3-acetoxypropy1]-benzimidazole.

EXAMPLE 6 When the following substituted o-phenylenediamines are used inplace of the 4-hydroxypropyl-o-phenylenediamine in the procedure ofExample 5, the corresponding listed products are obtained.

Starting material Products 4(2hydroxyethyl)-o-2-acetamid0-5-52-acet0xyethy11- phenylenediamine. benzimidazo e.4-hydroxymethyl-o- 2-acetamid0-5-[l-acetoxymethyl]- phenylenediamine.benzimidazole. 4(4-hydr0xybutyD-o- 2-acetamldo-5-[4-acetoxybutyl]-phenylenediamine. benzimidazole. 4(5-hydroxyamyD-o-2-acetamido-5-[5-acet0xyamyl]- phenylenedlamine. benzimidazole.4(6-hydroxyhexylyo- 2-acetamido-fi-[G-acetoxyhexyl]- phenylenediamine.benzimidazole.

EXAMPLE 7 When the following acyl halides are combined with cyanamide inplace of the isobutyryl chloride of Example 5, the corresponding listedproducts are obtained:

Starting material Products Allyl ehlcroformats 12-allylamido-5-[3-acetoxypropyl]- benzimidazole.2-methallylchloroformate 2-methallylamido-5-[3-acetoxypr0pyl1- (GA.46:8417 g. benzimidazole. Viny1chloroiormate(U.S.2-vinylamido-5-[3-acetoxypropyl]- Pat. 2,377,085). benzimidazole.Cyclopropylchloroformate. 2cycl0propylamido-6-[3-acetoxypropyl1-benzimidazole. Gyclobutylchlorotormate-.-2-cyclobutylamldO-5-{3acetoxypropyll benzimidazo e.Cyclopentylchloroformate 20yclopentylamido-5-[3-acetoxypropyl]- (C.A.50:4046a, 8477.). benzimidazole. l-Naphthylchloroiormate2-naphthylarm'do-5-[3-acetoxypr0py1] benzimidazole. Phenylchloroformate2-benzam1do-5-[3-aeet0xypropyl]- benzimidazole.

Available from Ohemetron Corp., Chicago, Ill.

EXAMPLE 8 Typical cattle bolus containing an anthelmintic describedherein Typical cattle bolus containing an anthelmintic described hereinGrams 2-carbomethoxyamino-5 [3-acetoxy propyl]-benzimidazole 2.0 Calciumphosphate 2.5 Maize starch 0.54 Talcum 0.14 Gum arabic 0.15 Magnesiumstearate 0.05

The calcium phosphate and the anthelmintic compound are thoroughlymixed, and the mixture reduced to a particle size finer than 60 mesh.About one-half of the starch is added, as an aqueous paste, and theresulting mixture granulated. The granules are passed through a #10 meshscreen and dried at 110-130 F. for about 8 hours. The dried materialsthen passed through a #16 mesh screen, The guar gum and the balance ofthe starch EXAMPLE 9 Typical sheep drench containing an anthelminticdescribed herein Parts by wt.

Z-carbomethoxyamino-S [3-acetoxypropylJ-benzimidazole 60 Terra AlbaEnglish 35.5 Tragacanth, U.S.P. 3.0 Sodium lauryl sulfate 1.5

Water What is claimed is: 1. A compound of the formula Y l O-(CHzhNH-C-R n 0 wherein R is straight chain alkoxy of 1 to 10 carbon atoms,branched chain alkoxy of 3 to 10 carbon atoms, cycloalkoxy of 3 to 10carbon atoms, alkenyloxy of 2 to 10 carbon atoms, alkynyloxy of 2 to 10carbon atoms, phenoxy, or naphthyloxy, a or [3;

Y is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms,straight chain alkenyl or alkynyl of 2 to 10 carbon atoms, or branchedchain alkenyl or alkynyl of 3 to 10 carbon atoms; and

n is an integer from 1 to 8.

2. A compound according to claim 1 wherein R is lower alkoxy from one tothree carbons, the benzene ring is 5-substituted, Y is lower alkyl fromone to three carbon atoms; and n is a whole integer from one to five.

3. A compound of claim 2 wherein the compound is, 2-calrbomethoxyamino-5(3 acetoxypropyl)-benzimidazo e.

4. A compound of claim 2 wherein the compound isZ-carboethoxyarnino-S-[Z acetoxyethyl]-benzimidazole.

5. A compound of claim 2 wherein the compound is 2-carbopropoxyamino-5[l acetoxymethyl1benzimidazole.

6. A compound of claim 1 wherein the compound is 2-carbobutoxyamino-5 [1acetoxymethy1]-benzimidazole.

7. A compound of claim 1 wherein the compound isZ-carbocyclopropyloxyamino-S [3 butyryloxypropylJ- benzimidazole.

8. A compound of claim 1 wherein the compound is 2-carboallyloxyamino-5[3 cyclobutylcarboxypropyl] benzimidazole.

9. A compound of claim 1 wherein the compound is 2-carbovinyloxyamino-5[4 cyclopropylcarboxybutyl]- benzimidazole.

References Cited UNITED STATES PATENTS 3,010,968 11/1961 LouX 260309.2

FOREIGN PATENTS 58,510 9/ 1967 Germany 260-3092 NATALIE TROUSOF, PrimaryExaminer US. Cl. X.R.

